Changes In Effective Refractory Period Research Articles

PO-455617-18 SHORT COUPLED PREMATURE ATRIAL COMPLEXES LEAD TO ADVERSE ATRIAL REMODELING AND ATRIAL FIBRILLATION IN A SWINE MODEL

Frequent premature atrial complexes (PACs) are associated with left atrial (LA) myopathy and atrial fibrillation (AF), however, the effect of coupling interval and irregularity on the ensuing atrial myopathy has not been tested. To explore the impact of coupling interval and regularity of atrial ectopics on the development of atrial remodeling and AF in a swine model. Thirty-five swine underwent baseline electrophysiologic study followed by pacemaker implantation and pacing from the lateral LA via the coronary sinus for 16 weeks in 4 groups: 1) controls without PACs (CTRL, n=10); 2) 50% paced PACs at a short coupling interval (CI) of 250ms (Short-PAC, n=10); 3) 50% PACs at a long CI of 400ms (Long-PAC, n=5); and 4) regular pacing at a faster mean atrial rate (130 beats/min) than during PACs (Reg-130, n=10). At the terminal study, a repeat electrophysiologic study was performed followed by sacrifice and histologic analysis. Structural changes: The Short-PAC group had the greater degree of LA dilation (terminal - baseline: Short-PAC 5.9±1.2cm2 vs. Long-PAC 3.9±0.5cm2 vs. Reg-130 3.0±1.0cm2 vs. CTRL 0.9±0.3cm2, p<0.001) and decrease in peak LA strain (terminal - baseline: Short-PAC -17.3±3.2% vs. Long-PAC -12.7±2.9% vs. Reg-130 -8.2±2.9% vs. CTRL -0.7±4.2%, p<0.001). Electrophysiologic changes: The Short-PAC group had slower LA conduction velocity than the Reg-130 and CTRL groups (Short-PAC 1.1±0.2m/s vs. Long-PAC 1.2±0.1m/s vs. Reg-130 1.3±0.1m/s vs. CTRL 1.5±0.2m/s, p<0.001); atrial effective refractory period (ERP) was only decreased in the Reg-130 group (terminal - baseline: Short-PAC -4.0±23.6ms vs. Long-PAC -8.7±17.9ms vs. Reg-130 -23.7±14.3ms vs. CTRL -3.2±23.7ms, p=0.09). Fibrosis: percent LA fibrosis was highest in the Short-PAC group followed by Long-PAC, Reg-130, and then CTRL groups (Figure, Panel A). AF induction: The Short-PAC group had the longest duration of induced AF (Panel B). In a swine model, frequent PACs can cause structural and electrical atrial remodeling with a heightened propensity for AF. PACs led to slow conduction and fibrosis without change in atrial ERP, suggesting a process distinct from tachy-pacing induced atrial remodeling. Moreover, PACs with short CIs resulted in a greater degree of LA remodeling and induced AF duration compared to PACs with long CIs. These findings suggest that frequent, short coupled PACs pose the highest risk for developing atrial remodeling and AF.

PO-01-001 SHORT COUPLED PREMATURE ATRIAL COMPLEXES LEAD TO ADVERSE ATRIAL REMODELING AND ATRIAL FIBRILLATION IN A SWINE MODEL

Frequent premature atrial complexes (PACs) are associated with left atrial (LA) myopathy and atrial fibrillation (AF), however, the effect of coupling interval and irregularity on the ensuing atrial myopathy has not been tested. To explore the impact of coupling interval and regularity of atrial ectopics on the development of atrial remodeling and AF in a swine model. Thirty-five swine underwent baseline electrophysiologic study followed by pacemaker implantation and pacing from the lateral LA via the coronary sinus for 16 weeks in 4 groups: 1) controls without PACs (CTRL, n=10); 2) 50% paced PACs at a short coupling interval (CI) of 250ms (Short-PAC, n=10); 3) 50% PACs at a long CI of 400ms (Long-PAC, n=5); and 4) regular pacing at a faster mean atrial rate (130 beats/min) than during PACs (Reg-130, n=10). At the terminal study, a repeat electrophysiologic study was performed followed by sacrifice and histologic analysis. Structural changes: The Short-PAC group had the greater degree of LA dilation (terminal - baseline: Short-PAC 5.9±1.2cm2 vs. Long-PAC 3.9±0.5cm2 vs. Reg-130 3.0±1.0cm2 vs. CTRL 0.9±0.3cm2, p<0.001) and decrease in peak LA strain (terminal - baseline: Short-PAC -17.3±3.2% vs. Long-PAC -12.7±2.9% vs. Reg-130 -8.2±2.9% vs. CTRL -0.7±4.2%, p<0.001). Electrophysiologic changes: The Short-PAC group had slower LA conduction velocity than the Reg-130 and CTRL groups (Short-PAC 1.1±0.2m/s vs. Long-PAC 1.2±0.1m/s vs. Reg-130 1.3±0.1m/s vs. CTRL 1.5±0.2m/s, p<0.001); atrial effective refractory period (ERP) was only decreased in the Reg-130 group (terminal - baseline: Short-PAC -4.0±23.6ms vs. Long-PAC -8.7±17.9ms vs. Reg-130 -23.7±14.3ms vs. CTRL -3.2±23.7ms, p=0.09). Fibrosis: percent LA fibrosis was highest in the Short-PAC group followed by Long-PAC, Reg-130, and then CTRL groups (Figure, Panel A). AF induction: The Short-PAC group had the longest duration of induced AF (Panel B). In a swine model, frequent PACs can cause structural and electrical atrial remodeling with a heightened propensity for AF. PACs led to slow conduction and fibrosis without change in atrial ERP, suggesting a process distinct from tachy-pacing induced atrial remodeling. Moreover, PACs with short CIs resulted in a greater degree of LA remodeling and induced AF duration compared to PACs with long CIs. These findings suggest that frequent, short coupled PACs pose the highest risk for developing atrial remodeling and AF.

Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation

AimsThe most efficient way to acutely restore sinus rhythm from atrial fibrillation (AF) is electrical cardioversion, which is painful without adequate sedation. Recent studies in various experimental models have indicated that optogenetic termination of AF using light-gated ion channels may provide a myocardium-specific and potentially painless alternative future therapy. However, its underlying mechanism(s) remain(s) incompletely understood. As brief pulsed light stimulation, even without global illumination, can achieve optogenetic AF termination, besides direct conduction block also modulation of action potential (AP) properties may be involved in the termination mechanism. We studied the relationship between optogenetic AP duration (APD) and effective refractory period (ERP) prolongation by brief pulsed light stimulation and termination of atrial tachyarrhythmia (AT). Methods and resultsHearts from transgenic mice expressing the H134R variant of channelrhodopsin-2 in atrial myocytes were explanted and perfused retrogradely. AT induced by electrical stimulation was terminated by brief pulsed blue light stimulation (470 nm, 10 ms, 16 mW/mm2) with 68% efficacy. The termination rate was dependent on pulse duration and light intensity. Optogenetically imposed APD and ERP changes were systematically examined and optically monitored. Brief pulsed light stimulation (10 ms, 6 mW/mm2) consistently prolonged APD and ERP when light was applied at different phases of the cardiac action potential. Optical tracing showed light-induced APD prolongation during the termination of AT. ConclusionOur results directly demonstrate that cationic channelrhodopsin activation by brief pulsed light stimulation prolongs the atrial refractory period suggesting that this is one of the key mechanisms of optogenetic termination of AT.

Endurance training increases ventricular refractoriness and wavelength of the cardiac impulse without participation of parasympathetic postganglionic neurons. A study in isolated rabbit heart

Abstract Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p&amp;lt;0.05). Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Ion Channel Trafficking: Control of Ion Channel Density as a Target for Arrhythmias?

The shape of the cardiac action potential (AP) is determined by the contributions of numerous ion channels. Any dysfunction in the proper function or expression of these ion channels can result in a change in effective refractory period (ERP) and lead to arrhythmia. The processes underlying the correct targeting of ion channels to the plasma membrane are complex, and have not been fully characterized in cardiac myocytes. Emerging evidence highlights ion channel trafficking as a potential causative factor in certain acquired and inherited arrhythmias, and therapies which target trafficking as opposed to pore block are starting to receive attention. In this review we present the current evidence for the mechanisms which underlie precise control of cardiac ion channel trafficking and targeting.

Effects of Na+ channel blockers on the restitution of refractory period, conduction time, and excitation wavelength in perfused guinea-pig heart.

Na+ channel blockers flecainide and quinidine can increase propensity to ventricular tachyarrhythmia, whereas lidocaine and mexiletine are recognized as safe antiarrhythmics. Clinically, ventricular fibrillation is often precipitated by transient tachycardia that reduces action potential duration, suggesting that a critical shortening of the excitation wavelength (EW) may contribute to the arrhythmic substrate. This study examined whether different INa blockers can produce contrasting effects on the rate adaptation of the EW, which would explain the difference in their safety profile. In perfused guinea-pig hearts, effective refractory periods (ERP), conduction times, and EW values were determined over a wide range of cardiac pacing intervals. All INa blockers tested were found to flatten the slope of ERP restitution, indicating antiarrhythmic tendency. However, with flecainide and quinidine, the beneficial changes in ERP were reversed owing to the use-dependent conduction slowing, thereby leading to significantly steepened restitution of the EW. In contrast, lidocaine and mexiletine had no effect on ventricular conduction, and therefore reduced the slope of the EW restitution, as expected from their effect on ERP. These findings suggest that the slope of the EW restitution is an important electrophysiological determinant which can discriminate INa blockers with proarrhythmic and antiarrhythmic profile.

Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts.

Ventricular arrhythmic and electrophysiological properties were examined during normokalaemia (5.2 mM [K+]), hypokalaemia (3 mM [K+]) or hypokalaemia in the presence of 0.1 or 2 mM heptanol in Langendorff-perfused mouse hearts. Left ventricular epicardial or endocardial monophasic action potential recordings were obtained during right ventricular pacing. Hypokalaemia induced ventricular premature beats (VPBs) in 5 of 7 and ventricular tachycardia (VT) in 6 of 7 hearts (P<0.01), prolonged action potential durations (APD90) from 36.2±1.7 to 55.7±2.0 msec (P<0.01) and shortened ventricular effective refractory periods (VERPs) from 44.5±4.0 to 28.9±3.8 msec (P<0.01) without altering conduction velocities (CVs) (0.17±0.01 m/sec, P>0.05), reducing excitation wavelengths (λ, CV × VERP) from 7.9±1.1 to 5.1±0.3 mm (P<0.05) while increasing critical intervals (CI, APD90-VERP) from −8.3±4.3 to 26.9±2.0 msec (P>0.001). Heptanol (0.1 mM) prevented VT, restored effective refractory period (ERP) to 45.2±2.9 msec without altering CV or APD, returning λ to control values (P>0.05) and CI to 8.4±3.8 msec (P<0.05). Heptanol (2 mM) prevented VPBs and VT, increased ERP to 67.7±7.6 msec (P<0.05), and reduced CV to 0.11±0.1 m/sec (P<0.001) without altering APD (P>0.05), returning λ and CI to control values (P>0.05). Anti-arrhythmic effects of heptanol during hypokalaemia were explicable by ERP changes, scaling λ and CI.

Selective Ablation of the Ligament of Marshall Reduces the Prevalence of Ventricular Arrhythmias Through Autonomic Modulation in a Cesium-Induced Long QT Canine Model.

The goal of this study was to investigate the effect of selective ablation of the ligament of Marshall (LOM) on ventricular arrhythmias (VAs). Previous studies have shown that selective stimulation of sympathetic elements of the LOM, the distalsegment of the ligament of Marshall that extends beyond the left superior pulmonary vein (LOMLSPV), might induceVAs. In protocol 1, the blood pressure and ventricular effective refractory period changes as a response to LOMLSPV stimulation and left stellate ganglion (LSG) stimulation were measured before and after LOMLSPV ablation in 8anesthetized dogs. In protocol 2, a total of 24 dogs were randomly divided into group 1 (cesium alone, n= 8), group 2 (cesium combined with LSG stimulation, n= 8), and group 3 (cesium combined with LSG stimulation after LOMLSPV ablation, n= 8). Early afterdepolarization amplitude, VA prevalence, and the tachycardia threshold (measured according to the dose of cesium administered) were compared among the groups. In protocol 1, both LOMLSPV stimulation and LSG stimulation significantly increased blood pressure and shortened the ventricular effective refractory period, both of which were significantly attenuated by LOMLSPV ablation. Inprotocol 2, compared with group 1, the prevalence of VAs and the early afterdepolarization amplitudes were significantly augmented in group 2 and were maintained at a comparable level in group 3. Furthermore, the tachycardia threshold in group 2 (0.625 mmol/kg) was significantly lower than that noted in groups 1 and 3 (both 1.000 mmol/kg; p< 0.05). LOMLSPV ablation reduced the prevalence of the VAs induced by cesium in combination with LSG stimulation, and the antiarrhythmic effect may involve the blockade of the sympathetic conduit between the LSG and the ventricles.

The Effects of Sympathetic Nerve Stimulation on Ventricular Electrophysiology in Long QT Syndrome‐1

Congenital long QT syndrome 1 (LQTS1) results from reduced slow activating delayed rectifier potassium channel (IKs) activity. Ventricular arrhythmias occur with increases in sympathetic tone which can cause sudden cardiac death (SCD). Underlying mechanisms are not understood but may include changes in electrical restitution (RT) – the relationship between action potential duration and diastolic interval. We aimed to examine the effects of sympathetic nerve stimulation (SNS) on effective refractory period (ERP), RT slope and inducibility of ventricular fibrillation (VF) in a pharmacological model of LQTS1. The innervated heart preparation from adult male guinea pigs (n=6, 450–550g) were used. ERP and LV apical and basal RT were measured using an extrastimulus protocol. Inducibility of VF was assessed with ventricular fibrillation threshold (VFT). Parameters were measured during baseline (BL) and SNS (3Hz, 1V) in control (Ctrl) and in the presence of the IKs blocker HMR1556 to mimic LQTS1 (HMR). Data are mean±SEM, analysed using Student's T‐Test (*vs BL, **vs Ctrl). During control, SNS significantly reduced ERP and VFT and increased RT slope but only at LV base, (Table). In the presence of HMR1556, the effects of SNS on ERP and VFT were augmented whilst the effect on RT was abolished. In conclusion, SNS increases susceptibility to VF which appears to be augmented in this pharmacological LQTS1 model and related to changes in ERP but not RT.Research support from the University of Leicester

Atrial Remodeling and the Substrate for Atrial Fibrillation in Rat Hearts With Elevated Afterload

Although arterial hypertension and left ventricular hypertrophy are considered good epidemiological indicators of the risk of atrial fibrillation (AF) in patients, the link between elevated afterload and AF remains unclear. We investigated atrial remodeling and the substrate for arrhythmia in a surgical model of elevated afterload in rats. Male Wistar rats (aged 3-4 weeks) were anesthetized and subjected to either partial stenosis of the ascending aorta (AoB) or sham operation (Sham). Experiments were performed on excised hearts 8, 14, and 20 weeks after surgery. Unipolar electrograms were recorded from the left atrial epicardial surface of perfused hearts using a 5×5 electrode array. Cryosections of left atrial tissue were retained for histological and immunocytochemical analyses. Compared to Sham, AoB hearts showed marked left atrial hypertrophy and fibrosis at 14 and 20 weeks postsurgery. The incidence and duration of pacing-induced AF was increased in hearts from AoB rats at 20 weeks postsurgery. The substrate for arrhythmia was associated with reduced vectorial conduction velocity and greater inhomogeneity in conduction but without changes in effective refractory period. Left atrial expression of the gap junction protein, connexin43, was markedly reduced in AoB compared with Sham hearts. Using a small-animal model, we demonstrate that elevated afterload in the absence of systemic hypertension results in increased inducibility of AF and left atrial remodeling involving fibrosis, altered atrial connexin43 expression, and marked conduction abnormalities.

Prevention and Reversal of Atrial Fibrillation Inducibility and Autonomic Remodeling by Low-Level Vagosympathetic Nerve Stimulation

We hypothesized that autonomic atrial remodeling can be reversed by low-level (LL) vagosympathetic nerve stimulation (VNS). Previously, we showed that VNS can be antiarrhythmogenic. Thirty-three dogs were subjected to electrical stimulation (20 Hz) applied to both vagosympathetic trunks at voltages 10% to 50% below the threshold that slowed sinus rate or AV conduction. Group 1 (n = 7): Programmed stimulation (PS) was performed at baseline and during 6-h rapid atrial pacing (RAP). PS allowed determination of effective refractory period (ERP) and AF inducibility measured by window of vulnerability (WOV). LL-VNS was continuously applied from the 4th to 6th hours. Group 2 (n = 4): After baseline ERP and WOV determinations, 6-h concomitant RAP+LL-VNS was applied. Sustained AF was induced by injecting acetylcholine (ACh) 10 mM into the anterior right ganglionated plexus (Group 3, n = 10) or applying ACh 10 mM to right atrial appendage (Group 4, n = 9). Group 1: The ERP progressively shortened and the ΣWOV (sum of WOV from all tested sites) progressively increased (p < 0.05) during 3-h RAP then returned toward baseline during 3-h RAP+LL-VNS (p < 0.05). Group 2: 6-h concomitant RAP+LL-VNS did not induce any significant change in ERP and ΣWOV. Group 3 and Group 4: AF duration (AF-D) and cycle length (AF-CL) were markedly altered by 3-h LL-VNS (Group 3: baseline: AF-D = 389 ± 90 s, AF-CL = 45.1 ± 7.8 ms; LL-VNS: AF-D = 50 ± 15 s, AF-CL = 82.0 ± 13.7 ms [both p < 0.001]; Group 4: baseline: AF-D = 505 ± 162 s, AF-CL = 48.8 ± 6.6 ms; LL-VNS: AF-D = 71 ± 21 s, AF-CL = 101.3 ± 20.9 ms [both p < 0.001]). LL-VNS can prevent and reverse atrial remodeling induced by RAP as well as suppress AF induced by strong cholinergic stimulation. Inhibition of the intrinsic cardiac autonomic nervous system by LL-VNS may be responsible for these salutary results.

TRPV1 Down-regulation in Syndrome X: Its Role in AF Susceptibility

Introduction: Research indicates that transient receptor potential vanilloid sub-family member 1 (TRPV1) expression in cardiac monocytes has a cardioprotective effect. TRPV1 null mice are more susceptible to post-ischaemic cardiac arrhythmia due to excessive inflammation and disproportional remodelling. Expression of TRPV1 is down-regulated in obese and diabetic (Syndrome X) mice andhumans, indicating these subjectsmayhave increased risk of cardiac arrhythmias such asAF. This study assessed changes in effective refractory period (ERP) of wild type (WT) and TRPV1 null (KO) mice in a glucose intolerance/obesity model. Methods: SixteenWT and 16 KOmicewere divided into equal groups receiving standard mouse or high fat diets. Following 18 weeks of ad libitum feeding a glucose tolerance test was performed and the cardiac tissue harvested. A multi-electrode array was utilised to assess the ERP at 100 and 200ms pacing lengths. Results: ERP data were ranked corresponding to the E r p n n a b

Ablation of Ligament of Marshall Attenuates Atrial Vulnerability to Fibrillation Induced by Inferior Left Atrial Fat Pad Stimulation in Dogs

The role of ligament of Marshall (LOM) in the mechanism of "vagal" atrial fibrillation (AF) is still unknown. To investigate the impact of LOM ablation on atrial vulnerability to AF induced by inferior left atrial fat pad (ILAFP) stimulation in dogs. AF inducibility and atrial effective refractory period (ERP) were elevated before and after LOM ablation in 8 of 14 dogs (the ablation group). Same protocol but without LOM ablation was conducted in the remaining 6 dogs (the control group). The activation patterns of LOM and left pulmonary veins (LPVs) during sustained AF were analyzed. The distribution of epicardial cholinergic nerve fibers between LOM and ILAFP was investigated in the control group. Ablation of LOM significantly attenuated AF inducibility (87.5% vs 33.3%, P < 0.001) and prolonged ERPs of the structures in contiguity with LOM (P < 0.05) in the ablation group. In contrast, there was no significant change in ERPs and AF inducibility in the control group. During sustained AF, fractionated atrial electrograms were more common in the LOM area than the LPVs (84% vs 18% of the analyzed episodes, P < 0.001). In 46.7% of the episodes with identifiable LOM spikes, atrial potentials, and LOM spikes were related in 2:1 or 3:2 pattern during the intermittent organized activity. Acetylcholinesterase staining revealed a close cholinergic nerved relationship between LOM and ILAFP. LOM plays a critical role in maintaining AF induced by stimulation of ILAFP. Ablation of LOM can markedly attenuate AF inducibility in this model.

Reverse Remodeling of the Atria After Treatment of Chronic Stretch in Humans: Implications for the Atrial Fibrillation Substrate

The aim of this report was to study the effect of chronic stretch reversal on the electrophysiological characteristics of the atria in humans. Atrial stretch is an important determinant for atrial fibrillation. Whether relief of stretch reverses the substrate predisposed to atrial fibrillation is unknown. Twenty-one patients with mitral stenosis undergoing mitral commissurotomy (MC) were studied before and after intervention. Catheters were placed at multiple sites in the right atrium (RA) and sequentially within the left atrium (LA) to determine: effective refractory period (ERP) at 10 sites (600 and 450 ms) and P-wave duration (PWD). Bi-atrial electroanatomic maps determined conduction velocity (CV) and voltage. In 14 patients, RA studies were repeated >or=6 months after MC. Immediately after MC, there was significant increase in mitral valve area (2.1 +/- 0.2 cm(2), p < 0.0001) with decrease in LA (23 +/- 7 mm Hg to 10 +/- 4 mm Hg, p < 0.0001) and pulmonary arterial pressures (38 +/- 16 mm Hg to 27 +/- 12 mm Hg, p < 0.0001) and LA volume (75 +/- 20 ml to 52 +/- 18 ml, p < 0.0001). This was associated with reduction in PWD (139 +/- 19 ms to 135 +/- 20 ms, p = 0.047), increase in CV (LA: 1.3 +/- 0.3 mm/ms to 1.7 +/- 0.2 mm/ms, p = 0.006; and RA: 1.0 +/- 0.1 mm/ms to 1.3 +/- 0.3 mm/ms, p = 0.002) and voltage (LA: 1.7 +/- 0.6 mV to 2.5 +/- 1.0 mV, p = 0.005; and RA: 1.8 +/- 0.6 mV to 2.2 +/- 0.7 mV, p = 0.09), and no change in ERP. Late after MC, mitral valve area remained at 2.1 +/- 0.3 cm(2) (p = 0.7) but with further decrease in PWD (113 +/- 19 ms, p = 0.04) and RA ERP (at 600 ms, p < 0.0001), with increase in CV (1.0 +/- 0.1 mm/ms to 1.3 +/- 0.2 mm/ms, p = 0.006) and voltage (1.8 +/- 0.7 mV to 2.8 +/- 0.6 mV, p = 0.002). The atrial electrophysiologic and electroanatomic abnormalities that result from chronic stretch due to MS reverses after MC. These observations suggest that the substrate predisposing to atrial arrhythmias might be reversed.

Vagal denervation and reinnervation after ablation of ganglionated plexi

Surgical ablation of ganglionated plexi has been proposed to increase efficacy of surgery for atrial fibrillation. This experimental canine study examined electrophysiologic attenuation and recovery of atrial vagal effects after ganglionated plexi ablation alone or with standard surgical lesion sets for atrial fibrillation. Dogs were divided into 3 groups: group 1 (n = 6) had focal ablation of the 4 major epicardial ganglionated plexi fat pads, group 2 (n = 6) had pulmonary vein isolation with ablation, and group 3 (n = 6) had posterior left atrial isolation with ablation. All fat pads were ablated. Sinus and atrioventricular interval changes during bilateral vagosympathetic trunk stimulation were examined before and both immediately and 4 weeks after ablation. Vagally induced effective refractory period changes and mean QRST area changes (index of local innervation) were examined in 5 atrial regions. Sinus and atrioventricular interval changes and heart rate variability decreased immediately after ablation, but only sinus interval changes were restored significantly after 4 weeks in all groups. Ablation-modified vagal effects on effective refractory period or QRST area changed heterogeneously in groups 1 and 2. In group 3, regional vagal effects were attenuated extensively postablation in both atria. Posterior left atrial isolation with ablation incrementally denervated the atria. In the long term, vagal stimulation increased QRST area changes relative to control values in all groups. Heart rate variability was also assessed. Ganglionated plexi ablation significantly reduced atrial vagal innervation. Restoration of vagal effects at 4 weeks suggests early atrial reinnervation.

Rate-dependence of atrial tachycardia effects on atrial refractoriness and atrial fibrillation maintenance

Although atrial-tachycardia remodelling is a significant atrial fibrillation (AF) promoting factor, little information is available about how atrial-tachycardia rate determines remodelling effects. This study assessed the effects of atrial tachypacing (ATP) over a range of clinically relevant rates on atrial electrophysiology and AF. Chronically instrumented dogs underwent sequential 7 day ATP at 400, 300, 200, and 160 bpm in random order with 2 day recovery intervals between periods of ATP. ATP at 400, 300, and 200 bpm significantly decreased atrial effective refractory period (ERP) by 41 +/- 2, 37 +/- 3, and 7 +/- 1 ms, respectively, with no significant effects at 160 bpm. Mean duration of induced AF was increased by 400 and 300 bpm ATP (404 +/- 284 and 410 +/- 283 s on day 4, respectively, vs. 12 +/- 4 s at baseline, P < 0.01), but not by 200 or 160 bpm ATP. ATP effects developed slowly with 200 bpm pacing, so we studied 5 week ATP at 200 and 160 bpm in additional dogs. ERP shortened gradually over 3 weeks at 200 bpm (131 +/- 5 ms baseline vs. 112 +/- 4 and 105 +/- 4 ms at 2 and 3 weeks, respectively), but no decrease occurred thereafter (5-week value: 104 +/- 3 ms) and AF duration was not significantly affected. No change in ERP or AF duration occurred at 160 bpm. Because of the limited effects of 200 bpm ATP on AF duration despite significant effects on ERP, we tested 200 bpm ATP effects in the presence of AF substrates. When 200 bpm ATP was induced in the presence of a fibrotic AF substrate induced by 2 weeks of ventricular tachypacing followed by 1 week recovery, no change in AF duration or atrial vulnerability occurred. However, when 200 bpm ATP was followed by 400 bpm ATP, the onset of remodelling and AF duration increases was accelerated. There is a non-linear relationship between atrial rate and the extent of atrial electrical remodelling. Remodelling at rates equivalent to paroxysmal supraventricular tachycardias in man is insufficient to promote AF alone or in the presence of an atrial fibrotic substrate, but can accelerate the remodelling and stabilization of AF when followed by faster atrial tachyarrhythmias.

Abstract 2023: Effect Of Chronic Stretch Reversal On Atrial Remodeling In Humans: Implications For The Atrial Fibrillation Substrate

Background : Chronic atrial stretch is an important determinant for atrial fibrillation (AF). Whether relief of stretch reverses the substrate predisposed to AF is unknown. Methods: Twenty one pts (31±9 years) with mitral stenosis (MS; MVA 0.89±0.1cm 2 ) undergoing mitral commissurotomy (MC) were studied by electrophysiological or electroanatomical mapping of both atria before and after MC. Multipolar catheters were placed in the lateral RA, Crista (CT), coronary sinus (CS), septal RA and LA. We measured: effective refractory period (ERP) at the LA appendage, septal/lateral LA roof, posterior LA, inferior LA, proximal/distal CS, low/high LRA and SRA at 600 and 450ms; P wave duration (PWD); double potentials (DP) or fractionated signals (FS) along CT; and conduction time along CS, LRA, inferior LA and LA roof. Activation and voltage maps were created to evaluate changes in conduction and voltage. In 14 pts, RA studies were repeated ≥6 months after MC. Results : Following MC, there was significant increase in MVA (2.1±0.3 cm 2, p&lt;0.0001) with decrease in LA (23±8 to 10±4 mmHg, p&lt;0.0001) and PA pressures (38±17 to 27±14mmHg, p&lt;0.0001) and LA volume (75±12 to 52±13ml, p&lt;0.0001). This was associated with no change in ERP and No. of DP/FS along the CT but with reduction in PWD (139±19 to 135±20ms, p=0.047), increase in conduction velocity (CV) in LA (1.3±0.3 to 1.7±0.2m/s, p=0.005) and RA (1.0±0.1 to 1.3±0.3 m/s, p=0.007) and increase in LA voltage (1.7±0.6 to 2.5±1.0 mV, p=0.05). Late after MC, there was a further decrease in PWD and RA ERP, with increase in RA CV (1.0±0.1 to 1.3±0.2 m/s, p=0.01) and voltage (1.7±0.7 to 2.8±0.6 mV, p=0.004) but with no change in other parameters. See table for details of pts studied late after MC. Conclusion: The electrophysiologic and electroanatomic abnormalities within the atria that result from MS are reversed after MC. These observations suggest that the substrate predisposing to atrial arrhythmias may be reversed. Results

The Effects of Nicorandil and Nifekalant, Which Were Injected into the Pericardial Space, for Transmural Dispersion of Repolarization in the Pig

Introduction: Some studies have reported that transmural dispersion of repolarization (TDR) is involved in the onset of ventricular arrhythmia. We investigated the effects of nicorandil (NIC) and nifekalant (NIF) injected into the pericardial space, on TDR and T waves in the pig. Methods and Results: We injected NIC 4 or 8 mg and NIF 50 or 100 mg at intervals into the pericardial space for eleven pigs. The effects of these drugs were investigated on the effective refractory period (ERP) between the endocardial and epicardial myocardial cells, as well as on QT time, QT peak-end (QTcpe) as an index of TDR, and T waveforms, respectively. QTcpe increased from 91 ± 21 to 116 ± 19 msec, 2.8 min after injection of NIC (p < 0.01), although corrected QT (QTc) interval did not changed. But 5.5 min after injection, QTc decreased while QTcpe recovered. T wave amplitude significantly increased, and epicardium ERP decreased. When NIF was injected, TDR decreased from 55 ± 10 msec to 44 ± 8 msec (p < 0.01) although QTc did not change. In a later phase, QTc increased (p < 0.01) and QTcpe recovered. T wave amplitude rapidly decreased and became negative. Conclusion: Injected into the pericardial space, NIC and NIF brought about certain changes in ERP, QT and T waveform. Furthermore, NIC increased TDR while NIF decreased TDR.

The Effects of Nicorandil and Nifekalant, Which Were Injected into the Pericardial Space, for Transmural Dispersion of Repolarization in the Pig

Introduction: Some studies have reported that transmural dispersion of repolarization (TDR) is involved in the onset of ventricular arrhythmia. We investigated the effects of nicorandil (NIC) and nifekalant (NIF) injected into the pericardial space, on TDR and T waves in the pig. Methods and Results: We injected NIC 4 or 8 mg and NIF 50 or 100 mg at intervals into the pericardial space for eleven pigs. The effects of these drugs were investigated on the effective refractory period (ERP) between the endocardial and epicardial myocardial cells, as well as on QT time, QT peak‐end (QTcpe) as an index of TDR, and T waveforms, respectively. QTcpe increased from 91 ± 21 to 116 ± 19 msec, 2.8 min after injection of NIC (p &lt; 0.01), although corrected QT (QTc) interval did not changed. But 5.5 min after injection, QTc decreased while QTcpe recovered. T wave amplitude significantly increased, and epicardium ERP decreased. When NIF was injected, TDR decreased from 55 ± 10 msec to 44 ± 8 msec (p &lt; 0.01) although QTc did not change. In a later phase, QTc increased (p &lt; 0.01) and QTcpe recovered. T wave amplitude rapidly decreased and became negative. Conclusion: Injected into the pericardial space, NIC and NIF brought about certain changes in ERP, QT and T waveform. Furthermore, NIC increased TDR while NIF decreased TDR.